Nicotine addiction is a complex behavioral phenomenon, characterized by alterations in synaptic transmission which contribute to a progression of addiction-related processes including reward, dependence, and relapse. The motivational and addictive properties of nicotine are critically reliant on activation of the mesolimbic dopamine (DA) circuitry, and most therapeutic approaches for smoking cessation have focused on this system. Endocannabinoid-related lipids (ERL) including oleoylethanolamide (OEA) modulate this circuitry by exerting a stimulus-dependent influence at these synapses, and drugs targeting OEA signaling have been proposed as an alternative therapeutic strategy for treating nicotine addiction. Both the OEA degradation pathway, mediated by fatty acid amide hydrolase (FAAH), as well as the presumptive OEA receptor peroxisome proliferator- activated receptor alpha (PPARalpha) has been heavily pursued as pharmacological targets for treating nicotine addiction, yet comparatively little is known about the mechanisms of OEA production. Activation of PPARalpha induces plasticity of cholinergic and glutamatergic transmission, which are both dysregulated following long- term nicotine self-administration. We propose that OEA-driven fluctuations between cholinergic plasticity (during depressed PPARalpha influence) and glutamatergic plasticity (during active PPARalpha signaling) create a negative spiral that plays an functional role in facilitating nicotine addictio. The role of NAPE-PLD in VTA cholinergic and glutamatergic plasticity will be functionally studied using electrophysiology techniques acquired in my K99 training phase in combination with in vivo micro dialysis. Having developed these techniques, we will then study the functional and behavioral role of NAPE-PLD following long-term nicotine self-administration the independent R00 phase of the project. This work will provide important insight into the mechanisms leading to reward dysfunction and nicotine dependence, and provide another avenue for pharmacotherapeutic development.